小柯机器人

美国加州大学圣迭戈分校Don W. Cleveland等研究人员合作发现，由EBV编码的EBNA1在簇状重复处进行染色体脆性位点断裂。2023年4月12日，《自然》杂志在线发表了这项成果。

研究人员表示，爱泼斯坦-巴尔病毒（EBV）是一种致癌性疱疹病毒，与几种淋巴细胞和上皮细胞来源的癌症有关。EBV编码EBNA1，它与EBV基因组中一簇20个拷贝的18碱基对回文序列结合。EBNA1还在非序列特异性位点与宿主染色体结合，从而使病毒得以持续存在。

研究人员表明EBNA1的序列特异性DNA结合域与一个EB病毒样18碱基对不完全回文序列的一组串联重复拷贝结合，包括人类11q23号染色体上的一个约21千碱基的区域。重复EBNA1结合位点的原位可视化显示了有丝分裂染色体上固有的脆弱DNA异常结构。研究人员证明，EBNA1结合水平的增加会引发11q23的剂量依赖性断裂，从而产生一个融合的含着丝粒片段和一个无着丝粒的片段，这两个片段在下一个细胞周期都会错位成微核。

在潜伏感染EBV的细胞中，将EBNA1的丰度提高到2倍就足以触发11q23的断裂。对EBV相关的鼻咽癌全基因组测序的检查显示，结构变体在11号染色体上高度富集。在38种癌症类型的2439个肿瘤中，EB病毒的存在也被证明与11号染色体重排的富集有关。这些研究结果确定了EB病毒和基因组不稳定性之间的一个以前未被重视的联系，其中EBNA1诱导的11q23的断裂引发了11号染色体结构变异的获得。

附：英文原文

Title: Chromosomal fragile site breakage by EBV-encoded EBNA1 at clustered repeats

Author: Li, Julia Su Zhou, Abbasi, Ammal, Kim, Dong Hyun, Lippman, Scott M., Alexandrov, Ludmil B., Cleveland, Don W.

Issue&Volume: 2023-04-12

Abstract: Epstein–Barr virus (EBV) is an oncogenic herpesvirus associated with several cancers of lymphocytic and epithelial origin1,2,3. EBV encodes EBNA1, which binds to a cluster of 20 copies of an 18-base-pair palindromic sequence in the EBV genome4,5,6. EBNA1 also associates with host chromosomes at non-sequence-specific sites7, thereby enabling viral persistence. Here we show that the sequence-specific DNA-binding domain of EBNA1 binds to a cluster of tandemly repeated copies of an EBV-like, 18-base-pair imperfect palindromic sequence encompassing a region of about 21 kilobases at human chromosome 11q23. In situ visualization of the repetitive EBNA1-binding site reveals aberrant structures on mitotic chromosomes characteristic of inherently fragile DNA. We demonstrate that increasing levels of EBNA1 binding trigger dose-dependent breakage at 11q23, producing a fusogenic centromere-containing fragment and an acentric distal fragment, with both mis-segregated into micronuclei in the next cell cycles. In cells latently infected with EBV, elevating EBNA1 abundance by as little as twofold was sufficient to trigger breakage at 11q23. Examination of whole-genome sequencing of EBV-associated nasopharyngeal carcinomas revealed that structural variants are highly enriched on chromosome 11. Presence of EBV is also shown to be associated with an enrichment of chromosome 11 rearrangements across 2,439 tumours from 38 cancer types. Our results identify a previously unappreciated link between EBV and genomic instability, wherein EBNA1-induced breakage at 11q23 triggers acquisition of structural variations in chromosome 11.

DOI: 10.1038/s41586-023-05923-x

Source: https://www.nature.com/articles/s41586-023-05923-x

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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